A. Background Regarding Nanoparticulate Compositions
Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto or associated with the surface thereof a non-crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate compositions of topiramate.
Methods of making nanoparticulate compositions are described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for “Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
Nanoparticulate compositions are also described, for example, in U.S. Pat. No. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” U.S. Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;” U.S. Pat. No. 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. Nos. 5,399,363 and 5,494,683, both for “Surface Modified Anticancer Nanoparticles;” U.S. Pat. No. 5,401,492 for “Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;” U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,451,393 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,466,440 for “Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;” U.S. Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,500,204 for “Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;” U.S. Pat. No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,543,133 for “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. 5,560,931 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188 for “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;” U.S. Pat. No. 5,571,536 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” U.S. Pat. No. 5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective Overcoats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” U.S. Pat. No. 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” U.S. Pat. No. 5,593,657 for “Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;” U.S. Pat. No. 5,622,938 for “Sugar Based Surfactant for Nanocrystals;” U.S. Pat. No. 5,628,981 for “Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;” U.S. Pat. No. 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen;” U.S. Pat. No. 6,221,400 for “Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;” U.S. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;” U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid Oral Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” U.S. Pat. No. 6,428,814 for “Bioadhesive nanoparticulate compositions having cationic surface stabilizers;” U.S. Pat. No. 6,431,478 for “Small Scale Mill;” U.S. Pat. No. 6,432,381 for “Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract,” U.S. Pat. No. 6,582,285 for “Apparatus for Sanitary Wet Milling,” U.S. Pat. No. 6,592,903 for “Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” and U.S. Pat. No. 6,656,504 for “Nanoparticulate Compositions Comprising Amorphous Cyclosporine and Methods of Making and Using Such Compositions,” all of which are specifically incorporated by reference.
In addition, U.S. Patent Application No. 20020012675 A1, published on Jan. 31, 2002, for “Controlled Release Nanoparticulate Compositions,” and WO 02/098565 for “System and Method for Milling Materials,” describe nanoparticulate active agent compositions, and are specifically incorporated by reference. None of these references describe nanoparticulate compositions of topiramate.
Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” U.S. Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and U.S. Pat. No. 5,776,496, for “Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.”
B. Background Regarding Topiramate
Topiramate is a sulfamate-substituted monosaccharide designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate, having the molecular formula C12H21NO8S, a molecular weight of 339.36, and the following structural formula:

Topiramate has a solubility in water of 9.8 mg/mL. It is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. Topiramate is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. See Physicians' Desk Reference, 57th Edition, pp. 2501 (2003). Topiramate is a white crystalline powder with a bitter taste.
Topiramate is an anticonvulsant intended for use as an antiepileptic drug. It is considered a broad spectrum anti-epileptic drug (AED) because it works to prevent both partial onset and generalized seizures. Epilepsy is a chronic condition characterized by recurrent, unprovoked seizures, or electrical disturbances in the brain that can alter a patient's consciousness, movement, or behaviors. Seizures are characterized as either partial or generalized, depending on where they originate in the brain. Epilepsy affects an estimated 2.3 million Americans and each year approximately 181,000 people in the United States are newly diagnosed with the condition.
Topiramate is chemically unrelated to any other anticonvulsant or mood regulating medication. Topiramate has potentially five mechanisms of action. They include the blockage of sodium channels (similar to many of the traditional epileptics), enhancement of GABA-a receptors (an inhibitory neurotransmitter), inhibitory effect on glutamate receptors, inhibition of L-type high-voltage calcium ion channels, and a diamox type effect. The relatively importance of these mechanisms in the functioning of topiramate is not clearly known but it does not appear that any other single AED shares these five properties.
Specifically, topiramate enhances a chemical substance that inhibits electrical activity in the brain, while blocking other substances that increase activity. Thus, topiramate appears to help balance electrical activity in the brain to reduce the frequency of seizures. Electrophysiological and biochemical studies of the effects of topiramate on cultured neurons have revealed three properties that may contribute to topiramate's antiepileptic efficacy. First, action potentials elicited repetitively by a sustained depolarization of the neurons are blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Second, topiramate increases the frequency at which γ-aminobutyrate (GABA) activates GABAA receptors, and enhances the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter. Third, topiramate antagonizes the ability of kainae to activate the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, non-NMDA) subtype of excitatory amino acid (glutamate) receptor, but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype.
Patients newly diagnosed with epilepsy are routinely prescribed multiple medications to treat their seizures. The results of a recent study demonstrate that topiramate has a significant effect on controlling seizures in newly diagnosed epilepsy patients, even when used as a stand-alone therapy. See “New Study Shows TOPAMAX® Used Alone Helps Many Newly-Diagnosed Epilepsy Patients Achieve Seizure Control,” (Dec. 11, 2002). Currently, topiramate is approved around the world as adjunctive (add-on) treatment for a variety of seizure types. In addition, more than 30 countries also have approved its use as stand-alone (monotherapy) treatment for epilepsy. In the United States, an application for this use was filed with the Food and Drug Administration in October 2002. If approved, topiramate will be the first AED indicated for initial monotherapy treatment for both partial and generalized tonic-clonic seizures in children and adults. Id.
Topiramate seems to be effective in some people with bipolar mood disorders that have not responded to lithium and/or other mood-stabilizers. Some people who have not been able to tolerate any antidepressant because of switches to mania or increased speed or intensity of cycling, or because of the development of mixed states, have been able to tolerate therapeutic doses of anti-depressants when taking topiramate. The weight loss that accompanies topiramate therapy in some instances is useful for those individuals who have gained weight while taking other mood stabilizing drugs. In some studies 20-50% of people taking topiramate lost weight.
Topiramate is also used for indications other than epilepsy. Among the most common uses of topiramate is the prevention of migraines. Less commonly than some of the other AEDs, topiramate is used for neuropathic pain relief. In some groups of patients, diabetics for example, the potential of weight loss is desirable and may therefore be a major reason for trying this medication for the treatment of diabetic neuropathic pain. Topiramate has also been shown in open label trials to be useful for treating essential type tremor. In addition, topiramate has been shown in multiple small trials to be effective in cluster headache. Finally, topiramate is also used by psychiatrists. A recent article in Lancet demonstrated a substantial benefit for using this medication to help alcoholics to quit drinking. See Johnson et al., “Oral topiramate for treatment of alcohol dependence: a randomized controlled trial,” Lancet, 361(9370):1666-7 (May 17, 2003).
Topiramate is commercially available as TOPAMAX® (Ortho-McNeil Pharmaceutical, Raritan, N.J.). TOPAMAX® is available in tablet of various sizes as well as a sprinkle form which can be used in those who cannot swallow. It is typically dosed twice daily. TOPAMAX® (topiramate) is available as 25 mg, 100 mg, and 200 mg round tablets for oral administration. The tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide (100 and 200 mg tablets), and polysorbate 80. Physicians' Desk Reference, 57th Edition, pp. 2501 (2003).
TOPAMAX® is indicated in the United States as adjunctive therapy for adults and children aged 2-16 with partial-onset seizures, primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.
Peak plasma concentrations of TOPAMAX® occur at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of TOPAMAX® from the tablet formulation is about 80% compared to a solution. The bioavailability of TOPAMAX® is not affected by food. Physicians' Desk Reference at 2502.
The pharmacokinetics of TOPAMAX® are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is reached in about 4 days in patients with normal renal function. Id.
TOPAMAX® is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Overall, oral plasma clearance is approximately 20 to 30 mL/min in humans following oral administration. Id.
The recommended total daily dose of TOPAMAX® as adjunctive therapy is 400 mg/day in two divided doses. In studies of adults with partial onset seizures, a daily dose of 200 mg/day has inconsistent effects and is less effective than 400 mg/day. It is recommended that therapy be initiated at 25-50 mg/day followed by titration to an effective dose in increments of 25-50 mg/week. Id.
In clinical trials of TOPAMAX® used as adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome, the most common side effects observed in children included excessive drowsiness, loss of appetite, fatigue, nervousness, difficulty with concentration/attention, weight loss, aggressive reaction and memory difficulties. In adults, the most common side effects were sleepiness, dizziness, poor coordination, speech difficulties, slowed thinking (psychomotor slowing), blurred or double vision, memory difficulties and changes in sensation. However, these effects were generally temporary. Physicians' Desk Reference at 2502-03.
TOPAMAX® lacks many of the more serious side effects seen with the older AEDs including a lack of known problems with bone marrow and an extremely small incidence of liver abnormalities apparently confined to patients with prior liver abnormalities. The drug does have a fairly common side effect of kidney stones (between 1-2%). It is also one of only two AEDs that have a statistically proven propensity to lose weight (Felbamate is the other). Other side effects include a change in taste, particularly with carbonated drinks, tingling in the extremities, and at times interference with mental function. The last side effect is highly dependent upon the rate of dose administration and is relatively uncommon among patients started at a low dose and advanced slowly. Dosing rates must be individualized based upon the patient and the other medications they are currently prescribed.
The following adverse events are related to topiramate in 5% or more of patients: ataxia, impaired concentration, confusion, dizziness, fatigue, paraesthesia, somnolence and abnormal thinking. Topiramate may also cause agitation and emotional lability (which may manifest as abnormal behavior) and depression. Less common adverse effects include amnesia, anorexia, aphasia, diplopia, nausea, nystagmus, speech disorder, alteration of the sense of taste, abnormal vision, and weight loss. Topiramate increases the risk of nephrolithiasis (formation of kidney stones).
There is a need in the art for topiramate formulations which can decrease frequency of dosing, improve clinical efficacy, and potentially reduce side effects. The present invention satisfies these needs.